View source for 5vad


==Crystal structure of human Prolyl-tRNA synthetase (PRS) in complex with inhibitor==
<StructureSection load='5vad' size='340' side='right'caption='[[5vad]], [[Resolution|resolution]] 2.36&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5vad]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5VAD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5VAD FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.36&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=91Y:3-[(cyclohexanecarbonyl)amino]-N-(2,3-dihydro-1H-inden-2-yl)pyrazine-2-carboxamide'>91Y</scene>, <scene name='pdbligand=PRO:PROLINE'>PRO</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5vad FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5vad OCA], [https://pdbe.org/5vad PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5vad RCSB], [https://www.ebi.ac.uk/pdbsum/5vad PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5vad ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/SYEP_HUMAN SYEP_HUMAN] Catalyzes the attachment of the cognate amino acid to the corresponding tRNA in a two-step reaction: the amino acid is first activated by ATP to form a covalent intermediate with AMP and is then transferred to the acceptor end of the cognate tRNA. Component of the GAIT (gamma interferon-activated inhibitor of translation) complex which mediates interferon-gamma-induced transcript-selective translation inhibition in inflammation processes. Upon interferon-gamma activation and subsequent phosphorylation dissociates from the multisynthetase complex and assembles into the GAIT complex which binds to stem loop-containing GAIT elements in the 3'-UTR of diverse inflammatory mRNAs (such as ceruplasmin) and suppresses their translation.<ref>PMID:1756734</ref> <ref>PMID:15479637</ref> <ref>PMID:23071094</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Prolyl-tRNA synthetase (PRS) is a member of the aminoacyl-tRNA synthetase family of enzymes and catalyzes the synthesis of prolyl-tRNAPro using ATP, l-proline, and tRNAPro as substrates. An ATP-dependent PRS inhibitor, halofuginone, was shown to suppress autoimmune responses, suggesting that the inhibition of PRS is a potential therapeutic approach for inflammatory diseases. Although a few PRS inhibitors have been derivatized from natural sources or substrate mimetics, small-molecule human PRS inhibitors have not been reported. In this study, we discovered a novel series of pyrazinamide PRS inhibitors from a compound library using pre-transfer editing activity of human PRS enzyme. Steady-state biochemical analysis on the inhibitory mode revealed its distinctive characteristics of inhibition with proline uncompetition and ATP competition. The binding activity of a representative compound was time-dependently potentiated by the presence of l-proline with Kd of 0.76 nM. Thermal shift assays demonstrated the stabilization of PRS in complex with l-proline and pyrazinamide PRS inhibitors. The binding mode of the PRS inhibitor to the ATP site of PRS enzyme was elucidated using the ternary complex crystal structure with l-proline. The results demonstrated the different inhibitory and binding mode of pyrazinamide PRS inhibitors from preceding halofuginone. Furthermore, the PRS inhibitor inhibited intracellular protein synthesis via a different mode than halofuginone. In conclusion, we have identified a novel drug-like PRS inhibitor with a distinctive binding mode. This inhibitor was effective in a cellular context. Thus, the series of PRS inhibitors are considered to be applicable to further development with differentiation from preceding halofuginone.

Discovery of a novel prolyl-tRNA synthetase inhibitor and elucidation of its binding mode to the ATP site in complex with l-proline.,Adachi R, Okada K, Skene R, Ogawa K, Miwa M, Tsuchinaga K, Ohkubo S, Henta T, Kawamoto T Biochem Biophys Res Commun. 2017 Jun 24;488(2):393-399. doi:, 10.1016/j.bbrc.2017.05.064. Epub 2017 May 10. PMID:28501621<ref>PMID:28501621</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5vad" style="background-color:#fffaf0;"></div>

==See Also==
*[[Aminoacyl tRNA synthetase 3D structures|Aminoacyl tRNA synthetase 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Okada K]]
[[Category: Skene RJ]]